Inhibition of LPS induced iNOS, COX-2 and cytokines expression by kaempferol-3-O-${\beta}$-D-sophoroside through the $NF{-\kappa}B$ inactivation in RAW 264.7 cells

Kaempferol-3-O-${\beta}$-D-sophoroside의 RAW 264.7 세포에서 $NF{-\kappa}B$ 억제를 통한 LPS에 의해 유도되는 iNOS, COX-2 및 cytokine들의 발현 저해효과

  • Park, Seung-Jae (Department of pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University) ;
  • Shin, Ji-Sun (Department of pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University) ;
  • Cho, Woong (Department of pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University) ;
  • Cho, Young-Wuk (Department of physiology, College of Medicine, Kyung-Hee University) ;
  • Ahn, Eun-Mi (Department of Herbal Food Science, Daegu Haany University) ;
  • Baek, Nam-In (Department of Life Science, Kyung-Hee University) ;
  • Lee, Kyung-Tae (Department of pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University)
  • Published : 2008.06.30

Abstract

In the present study, we investigated the anti-inflammatory effects by kaempferol-3-O-${\beta}$-D-sophoroside (KS) isolated from Sophora japonica (Leguminosae) on the lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin ($PGE_2$) production by RAW 264.7 cell line compared with kaempferol. KS significantly inhibited the LPS-induced NO and $PGE_2$ production. Consistent with these observations, KS reduced the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein and mRNA levels in a concentration-dependent manner. In addition, the release and the mRNA expression levels of tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$) and interleukin-6 (IL-6) were also reduced by KS. Moreover, KS attenuated the LPS-induced activation of nuclear factor-kappa B ($NF{-\kappa}B$), a transcription factor necessary for pro-inflammatory mediators, iNOS, COX-2, $TNF-{\alpha}$ and IL-6 expression. These results suggest that the down regulation of iNOS, COX-2, $TNF-{\alpha}$, and IL-6 expression by KS are achieved by the downregulation of $NF{-\kappa}B$ activity, and that is also responsible for its anti-inflammatory effects.

Keywords

References

  1. Song, E. K., Hur, H., and Han, M. K. (2003) Epigallocatechin gallate prevents autoimmune diabetes induced by multiple low doses of streptozotocin in mice. Arch. Pharm. Res. 26: 559-563 https://doi.org/10.1007/BF02976881
  2. Kashiwada, Y., Nonada, G., Nishioka, I., Chang, J. J., and Lee, K. H. (1992) Antitumor agents, 129. tannins and related compounds as selective cytotoxic agents. J. Nat. Prod. 55: 1033-1043 https://doi.org/10.1021/np50086a002
  3. Kashiwada, Y., Nonada, G., Nishioka, I., Ballas, L. M., Jiang, J. B., Janzeng, W. P., and Lee, K. H. (1992) Tannins as selective inhibitors of protein kinase C. Bioorg. Med. Chem. Letters. 2: 239-244 https://doi.org/10.1016/S0960-894X(01)81072-6
  4. Yu, H. N., Yin, J. J., and Shen, S. R. (2004) Growth inhibition of prostate cancer cells by epigallocatechin gallate in the presence of $Cu^{++}$. J. Agric. Food Chem. 52: 462-466 https://doi.org/10.1021/jf035057u
  5. Theoharides, T. C., Alexandrakis, M., Kempuraj, D., and Lytinas, M. (2001) Anti-inflammatory actions of flavonoids and structural requirements for new design. Int. J. Immunopathol. Pharmacol. 14: 119-127
  6. Shen. S. C., Ko, C. H., Hsu, K. C., and Chen, Y. C. (2004) 3-OH flavone inhibition of epidermal growth factor-induced proliferation through blocking prostaglandin E2 production. Int. J. Cancer. 108: 502-510 https://doi.org/10.1002/ijc.11581
  7. Waffo-Teguo, P., Hawthorne, M. E., Cuendet, M., Merillon, J. M., Kinghorn, A. D., Pezzuto, J. M., and Mehta, R. G. (2001) Potential cancer chemopreventive activities of wine stilbenoids and flavans extracted from grape (Vitis vinifera) cell cultures. Nutr. Cancer. 40: 173-179 https://doi.org/10.1207/S15327914NC402_14
  8. Du, J., He, Z. D., Jiang, R. W., Ye, W. C., Xu, H. X., and But, P. P. (2003) Antiviral flavonoids from the root bark of Morus alba L. Phytochemistry. 62: 1235-1238 https://doi.org/10.1016/S0031-9422(02)00753-7
  9. Garcia-Mediabilla, V., Crespo, I., Collado, P. S., Esteller, A., Sanchez-Campos, S., Tunon, M. J., and Gonzalez-Gallego, J. (2007) The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and downregulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur. J. Pharmacol. 28: 221-229
  10. Kowalski, J., Samojedny, A., Paul, M., Pietsz, G., and Wilczok, T. (2005) Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol. Rep. 57: 390-394
  11. Willoughby, D. A. (1975) Human arthritis applied to animal models. Towards a better therapy. Ann. Rheum. Dis. 34: 471-478 https://doi.org/10.1136/ard.34.6.471
  12. Axtelle, T. and Pribble, J. (2001) IC14, a CD14 specific monoclonal antibody is a potential treatment for patients with severe sepsis. J. Endotoxin. Res. 7: 310-314 https://doi.org/10.1177/09680519010070040201
  13. Lee, E. S., Ju, H. K., Moon, T. C., Lee, E., Jahng, Y., Lee S. H., Son, J. K., Baek, S. H. and Chang, H. W. (2004) Inhibition of nitric oxide and tumor necrosis factor-a (TNF-a) production by propenone compound through blockade of nuclear factor (NF)-eB activation in cultured murine macrophage. Biol. Pharm. Bull. 27: 617-620 https://doi.org/10.1248/bpb.27.617
  14. MukIS, N., Ishikawa, Y., Ikeda, N., Fujioka, N., Watanabe, S. and Kuno, K. (1996) Novel insight into molecular mechanism of endotoxin shock; biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-kapperB and regulation of cytokine production/action through beta2 integrin in vivo. J. Leukoc. Biol. 59: 145-151 https://doi.org/10.1002/jlb.59.2.145
  15. Lazarov, S., Balutsov, M. and lanev, E. (2000) The role of bacterial endotoxins, receptors and cytokines in the pathogenisis of septic(endotoxin) shock. Vutr. Boles. 32: 33-40
  16. Scott, M. G. and Hancock, R. E. (2000) Cationic antimicrobial peptides and their multifunctional role in the immune system. Crit. Rev. Immunol. 20: 407-431
  17. Liu, S.F. and Malik, A.B. (2005) $NF-_{\kappa}B$ activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 290: L622-L645 https://doi.org/10.1152/ajplung.00477.2005
  18. Michael, E. E. (1986) Manual of cultivated broad-leaved tress & shrubs. Volume, Timber Press, Protland, Oregon. pp. 325-327
  19. Harborne, J. B. and Wiliam, C. A. (2000) Advances in flavonoid research since 1992. Phytochemistry. 55: 481-504 https://doi.org/10.1016/S0031-9422(00)00235-1
  20. Wenzel, U., Kuntz, S., Brendel, M. D. and Daniel, H. (2000) Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. Cancer Res. 60: 3823-3831
  21. Nature, and Medicine study association of Korea, Life-Chinese Medicine 'Folk Medicine. DongBu-MunHwaSa. pp. 21 (1985)
  22. Kim, H. J., Kim, M. K., Shim, J. G., Yeom, S. H., Kwon, S. H. and Lee, M. W. (2004) Anti-oxidative phenolic compounds from Sophorae fructus. Nat. Prod. Sci. 10: 330-334
  23. Surh, Y. J., Chun, K. S., Cha, H. H., Han, S. S., Keum, Y. S., Park, K. K. and Lee, S. S. (2001) Molecular mechanism underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat. Res. 480-481: 243-268 https://doi.org/10.1016/S0027-5107(01)00183-X
  24. Park, S. J., Kim, J. Y., Jang, Y. P., Cho, Y. W., Ahn, E. M., Beek, N. I., Lee, K. T. (2007) Inhibition of LPS induced iNOS, COX-2 and cytokines expression by $genistein-4'-O-{\alpha}-L-rhamnopyranosyl-(1-2)-{\beta}-D-glucopyranoside$ through the $NF-_{\kappa}B$ inactication in RAW 264.7 cells. Kor. J. Pharmacogn. 38: 339-348
  25. Iontcheva, I., Amar, S., Zawawi, K. H., Kantarci, A. and Van Dyke, T. E. (2004). Role for moesin in lipopolysaccharidestimulated signal transduction. Infect Immun. 72: 2312-2320 https://doi.org/10.1128/IAI.72.4.2312-2320.2004
  26. Stuehr, H. H. J., Kwon, N. S., Weise, M. and Nathan, C. (1991) Purification of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN- containing flavoprotein. Proc. Natl. Sci. USA. 88: 7773-7777
  27. McCartney-Francis, N., Allen, J. B., Mizel, D. E., Albina, J. E., Xie, Q. W., Nathan, C. F. and Wahl, S. M. (1993) Suppression of arthritis by an inhibitor of nitic oxide synthase. J. Exp. Med. 178: 749-754 https://doi.org/10.1084/jem.178.2.749
  28. Weisz, A., Cicatiello, I. and Esumi, H. (1996) Regulation of the mouse inducible-type nitric oxide synthase gene promoter by interferon-gamma, bacterical lipopolysaccharide and NG-monomethyl-L-arginene. Biochem. J. 316: 209-215 https://doi.org/10.1042/bj3160209
  29. Masferrer, J., Zweifel B. S., Manning, P. T., Hauser, S. D., Leahy, K. M., Smith, W. G., Isacson, P. C. and Seibert, K. (1994) Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 91: 3228-3232
  30. Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L. and Ksakson, P. (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. U.S.A. 91: 12013-12017
  31. Feldmann, M., Brennan, F. M. and Maini, R. N. (1996) Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14: 397-440 https://doi.org/10.1146/annurev.immunol.14.1.397
  32. Karin, M. and Ben-Neriah, Y. (2000) Phosphorylation meets ubiquitination: the control of NF-B activity. Annu. Rev. Immunol. 18: 621-663 https://doi.org/10.1146/annurev.immunol.18.1.621